title: A caspase-dependent cleavage of CDC25A generates an active fragment activating cyclin-dependent kinase 2 during apoptosis.
abstract: The cellular level of the CDC25A phosphatase is tightly regulated during both the normal and genotoxic-perturbed cell cycle. Here, we describe a caspase-dependent cleavage of this protein at residue D223 in non-genotoxic apoptotic conditions. This specific proteolysis generates a catalytically active C-terminal fragment that localizes to the nuclear compartment. Accumulation of this active CDC25A fragment leads to reduced inhibitory phosphorylation of the CDC25A substrate cyclin-dependent kinase 2 (CDK2) on Tyr15. Moreover, CDK2 was found stably associated with this fragment, as well as with an ectopically expressed CDC25A224-525 truncation mutant that mimicks the cleavage product. Ectopic expression of this mutant induced CDK2 Tyr15 dephosphorylation, whereas its catalytically inactive version did not. Finally, this 224-525 mutant initiated apoptosis when transfected into HeLa cells, whereas its catalytic inactive form did not. Altogether, this study demonstrates for the first time that caspase-dependent cleavage of CDC25A is a central step linking CDK2 activation with non-genotoxic apoptotic induction.
authors.affiliation: Département Oncogenèse et Signalisation dans cellules Hématopoïétiques, INSERM U563-IFR30, Centre de Physiopathologie Toulouse-Purpan, CHU Purpan, 31024 Toulouse Cedex 3, France.
authors.forename: A
authors.initials: A
authors.lastname: Mazars
authors.forename: A
authors.initials: A
authors.lastname: Fernandez-Vidal
authors.forename: O
authors.initials: O
authors.lastname: Mondesert
authors.forename: C
authors.initials: C
authors.lastname: Lorenzo
authors.forename: G
authors.initials: G
authors.lastname: Prévost
authors.forename: B
authors.initials: B
authors.lastname: Ducommun
authors.forename: B
authors.initials: B
authors.lastname: Payrastre
authors.forename: C
authors.initials: C
authors.lastname: Racaud-Sultan
authors.forename: S
authors.initials: S
authors.lastname: Manenti
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D020298:U937 Cells; D020687:cdc25 Phosphatases / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D051357:Cyclin-Dependent Kinase 2; D020687:cdc25 Phosphatases; D020169:Caspases